Anti-parasitic 5-nitrothiazolyl oxodiazacycloalkane compositions



United States Patent 3,298,914 ANTI-PARASITIC S-NITROTHIAZOLYL OX0- DIAZACYCLOALKANE COMPOSITIONS Paul Schmidt, Therwil, Max Wilhelm, Allschwil, and Kurt Eichenberger, Therwil, Switzerland, assignors to Cib'a Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed July 12, 1966, Ser. No. 564,536 Claims priority, application Switzerland, May 30, 1962,

,604/ 62 8 Claims. (Cl. 16753) This is a continuation-in-part of our copending application Serial No. 485,927, filed September 8, 1965 which is a continuation-in-part of Serial No. 447,868, filed April 13, 1965 (now abandoned), which in turn is a continuation-in-part of our application Serial No. 391,294, filed August 21, 1964 (now abandoned), which in turn is a continuation-in-part of our application, Serial No. 282,589, filed May 23, 1963 (now abandoned).

The present invention relates to new 2-oxo-l,3-diazocycloalkanes. Especially it concerns 2-.oxo-1,3-diazo-cycloalkanes of the formula in which T represents a -nitrothiazolyl-2 radical; Z stands for a lower alkylene radical which separates the two nitrogen atoms by 2 to 5, preferably by 3 or 4 but above all by 2, carbon atoms and which may be substituted by one or several, possibly substituted, hydrocarbon radicals, and R represents a hydrogen atom, an acyl radical or an unsubstituted or substituted hydrocarbon radical of aliphatic character, above all a lower alkyl radical which is unsubstituted or substituted by a hydroxy group or by a tree or substituted amino group, or a lower alkenyl .or an araliphatic radicaland, as the case may be, their salts.

Particularly suitable as hydrocarbon radicals are lower alkyl, lower alkenyl, phenyl and phenyl-lower alkyl radicals such as benzylor phenylethyl radicals. These phenyl or phenyl-lower alkyl groups may be substituted especially by lower alkyl groups, lower alkoxy groups such as methoxy, ethoxy, propoxy or butoxy groups, or halogen atoms such as chlorine or bromine, trifluoromethyl groups or nitro groups. In the foregoingand following lower alkyl radicals are preferably those which contain up to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl groups. Lower alkenyl radicals are above all allyl or methallyl radicals. As araliphatic radicals there may be mentioned above all phenyl-lower alkyl groups, such as benzyl, l-phenylethyl or 2-phenylethyl radicals. The araliphatic radicals may be substituted on the carbon atoms, especially on the aryl radicals by halogen atoms such as chlorine or bromine, the pseudohalogen trifiuoromethyl, lower alkyls such as methyl or ethyl,'by lower alkoxy groups such as methoxy, ethoxy or methylenedioxy or by nitro groups.

' Substituted amino groups are monosubstituted or preferably disubstituted amino groups, and the substituents may be above all lower alkyl, lower alkenyl, lowercycloalkyl radicals, or alkylene, mono-oxaor mono-azaalkylene radicals having from 4 to 8 carbon atoms. There may be mentioned, for example, monoor di-lower alkylamino groups such as methylamino, ethylamino, dimethylamino, diethylamino, dipropylamino, cyclohexylamino, methylcyclohexylamino, ethyl-cyclopentylamino, diallylamino, allyl-ethylamino or methallylamino groups, pyrrolidino, piperidino, morpholino, hexaor heptamethyleneamino,

piperazino, N-lower alkyl piperazino or N-(hydroxy-lower alkyl)-piperazino groups such as N-methyl-piperazino or propionic, butyric, trimethylacetic or valeric acid or above all acetic acid, or of substituted lower alkanoic acids, such as halogen-lower allcanoic acids, for example monoor dichloro-acetic acid or trifluoracetic acid. As further suitable acyl radicals there may be mentioned the radicals of aromatic or araliphatic oarboxylic acids, such as those of benzoic acids or phenyl-lower alkaneor -alkene acids, for example phenylacetic acids, phenylpropionic acids, or

.cinnamic acids; also the'acyl radicals of heterocyclic carboxylic acids, for example of pyridine-, furanor thiophene-carboxylic acids. The aromatic or heterocyclic rings of these carboxylic acids may also be substituted, for example by halogen, lower alkoxy, lower alkyl, trifluoromethyl, nitro or amino groups.

The new compounds may be further substituted, more especially in the 4-p.osition of the thiazole ring, for example, by lower alkyl radicals, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl, lower alkenyl radicals such as allyl or methallyl, or by phenyl groups, and the phenyl radicals themselves may likewise be sub- 1 stituted, for example as indicated above for the phenyl groups.

The radical Z is especially an unsubstituted ethylene- (1,2)-11adical or an ethylene-(1,2) radical substituted by lower alkyl radicals, or a propylene-(1,2), butylene-( 1,4), or pentylene-(l,5) radical which may be substituted by lower alkyl radicals.

The new compounds possess valuable pharmacological, especially antiparasitic and antibacterial properties. They are primarily suitable for the treatment of protozoic and helminthic conditions, for example in infested animals, for example mice, against Gram-negative bacteria, for example Salmonella typhi or Call bacilli, such as Escherichia coli. As has been been demonstrated by experiments on hamsters, for example, the new compounds are particularly effective against trichomonades and amoebae, and for example in mice and sheep against schistosomes. The new new compounds are also valuable intermediates for the manufacture of other useful substances.

Especially valuable are the compounds of the formula in which R stands for the radical of the formula and m and n each stands for an integer from 0 to 5 and alk for a straight or branched lower alkylene radical separating the two nitrogen atoms by 2 to 5 carbon atoms, the compounds of the above mentioned Formula II in which n and alk have the (meanings given above and R represents a hydroxy-lower alkyl radical, especially the "hydroxymethyl radical, the compounds of the above mentioned Formula IIin which n and alk have the mean- Patented Jan. 17, 1967.

ings given above, R stands for a di-lower alkyl-aminolower alkyl radical, especially a di-lower alkyl-aminomethyl radical, and their acid addition salts, and the compounds of the Formula II in which n and alk have the meanings given above and R stands for lower alkanoyl. Especially preferred groups of compounds are those of the formula in which p stands for an integer from 2 to 4 and R for a hydrogen atom, those of Formula III in which p has the meaning given and R stands for a hydroxy-lower alkyl radical, especially for the hydroxymethyl radical, those of the Formula III in which p has the meaning given and R represents a di-lower alkl-amino-lower alkyl radical, especially a di-lower alkyl-aminomethyl radical, and their acid addition salts, and the compounds of Formula III in which p has the meaning given and .R stands for a lower alkanoyl radical, such as the acetyl radical.

A specially good action against amoebae and schistosomes exert the 1-[5-nitro-thiazolyl-(2)] 2 oxotetrahydro-imidazole, the 1-[5 -nitrothiazolyl-(2) ]-2oxohexahydropyrimidine and the 1-[5-nitrothiazolyl-(2)]-2-oxo- 3-acetyl-tetrahydroimidazole.

The new compounds are manufactured by known methods.

For example, the new compounds are obtained when a compound of the general formula where T, Z and R have the above meaningsis subjected to intramolecular condensation accompanied by elimination of hydrochloric acid and, if desired, in a compound so obtained the radical R is introduced into the 3-position of the diaza-cycloalkaue ring.

The intro molecular condensation (cyclisation) is preferably performed by heating, advantageously in the presence of a polar solvent, above all water, and/or in the presence of a condensing agent, especially a basic condensing agent such as an alkali metal acetate or carbonate, if desired in a suitable solvent, such as an acid amide, for example dimethylformamide.

According to another process for manufacture of the new compounds a compound of the general formula where R and Z have the above meanings and T is a thiazolyl-Z radical which is unsubstituted in position 5- is nitrated. Nitration is carried out in the manner known in thiazole chemistry, for example by treatment with a mixture of concentrated sulfuric and concentrated nitric acid or with the mixed anhydride of nitric acid and a carboxylic acid, such as acetic acid, Any phenyl groups present may be nitrated at the same time.

The introduction of a substituent R into a compound in which R is a hydrogen atom is performed in the known manner, for example in the manufacture of compounds in which the substituent R is an unsubstituted or substituted hydrocarbon radical of aliphatic character, such as a lower alkyl radical which is unsubstituted or substituted by a hydroxyl group or by a free or substituted amino group, or a lower alkenyl or an araliphatic radical and in which the substituent R contains no hydroxyl or amino groups or in which any hydroxyl or amino groups present in R are separated from the cyclic nitrogen atom by at least 2 carbon atoms, by reaction with a halide of the formula RX in which R has the above meaning and X represents a halogen atom, such as a chlorine atom. If desired, this operation is performed with a metal salt such as an alkali metal salt of the 3- unsubstituted 2-oxotetrahydro-imidazole, or in the presence of a basic condensing agent, especially a condensing agent capable of forming metal salts, such as an amide, hydride, hydrocanbon, hydroxide, alcoholate or carbonate of an alkali metal.

Compounds in which R is a methyl radical that carries a hydroxyl group or a free or substituted amino group, especially a hydroxymethyl or secondary or tertiary aminomethyl radical are obtained by reaction with formaldehyde, if desired or required in the presence-of ammonia or of an amine.

Introduction of the hydroxymethyl group is achieved by a simple reaction with formaldehyde, if desired in the form of a formaldehyde donor, such as trioxymethylene or paraforrnaldehyde, advantageously in the presence of a basic condensing agent, such as an alkali metal hydroxide or carbonate, or of a tertiary amine or quaternary ammonium hydroxide, such as triethylamine or benzyltrimethyl ammonium hydroxide.

The a-minomethyl group is advantageously introduced by the Mannich reaction, for example with formaldehyde, with the use of a salt of ammonia or of an amine. Also in this case the formaldehyde may be used in the form of a donor, such as trioxymethylene or parafonmaldehyde, if desired in the presence of an acid.

The introduction of an acyl radical in 3-position of a 3-unsubstituted 1-[5-nitrothiazolyl] 1,3 diazacycloalkane is performed e.g. by reaction of a compound of the formula in which T and Z have the meanings given above, with reactive derivatives of acids, above all the halides, such as chlorides or bromides, or their anhydrides. It is advantageous to use a condensing agent. Thus bases such as pyridine or acylate ions promote the reaction of the acid anhydrides, and bases, such as pyridine or alkali, for example sodium carbonate, promote the reaction of the acid halides.

The above-mentioned reactions are performed in the usual manner.

Depending on the reaction conditions and starting materials used, the final products having substituted or unsubstituted amino groups are obtained in the free form or in the form of their salts which arelikewise included in the present invention. A resulting amine can be converted into a salt thereof in the usual manner by reaction with an organic or inorganic acid, especially one that is suitable for the formation of therapeutically acceptable salts. On the other hand, a resulting salt can be converted into the free compound in the usual manner, for example by treatment with a basic agent or ion exchange resin. Acids, suitable for the formation of therapeutically acceptable salts, are for instance hydrohalic, sulfuric or phosphoric acids, nitric or perchloric acid; alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids such as formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic or pyruvic' acid; phenylacetic, benzoic, para-aminobenzoic, anthranilic, para-hydroxybenzoic, salicyclic, para-aminosalicyclic or embonic acid, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic acid, haloge'nbenzenesulfonic, toluenesulfonic, naphthalenesulfonic acids or sulfanilic acid; methionine, tryptophan, lysine or arginine.

These or other salts of the neW compounds, for example, the picrates, can also be used for purification of the amines obtained; the amines are converted into salts, the salts are separated and the amines are liberated from the salts. In view of the close relationship between the free amino-compounds and the amino-compound inthe form of a salt thereof, whenever a free amine is referred to in this context, a corresponding salt is also intended provided such is possible or applicable under the circumstances.

The invention further includes any variant of the present process in which an intermediate product obtainable at any stage of the process is used as starting material and any remaining steps are carried out, or the process is discontinued at any stage thereof, or in which a starting material is formed under the reaction conditions or is used in the form of a salt.

It is advantageous to use starting materials that give rise to the final products described above as being particularly valuable. v

The starting materials used are known or, insofar as they are new, they can be prepared by known methods.

The new compounds may be used for example in the form of pharmaceutical preparations which contain them in the free form or in the form of their salts in conjunction or admixture with an organic or inorganic solid or liquid pharmaceutical excipient suitable for enteral, parenteral or local administration. Suitable excipients are substances that do not react with the new compounds, for example water, gelatine, lactose, starches, magnesium stearate, talcum, vegetable oils, benzyl alcohol, gums, polyalkyleneglycols, white petroleum jelly, cholesterol or other known medicinal excipient. The pharmaceutical preparations may be, for example, tablets, dragees, ointments or creams, or in liquid form solutions, suspensions or emulsions. They may be sterilized and/ or contain assistants such as preserving stabilizing, wetting or emulsifying agents, salts for regulating the osmotic pressure, or buffers. They may also contain further therapeutically valuable substances, such as for example 2-sulfanilamido- 6-chloropyrazine. The above-mentioned products may also be used in conjunction with conventional animal fodders or vehicles as fodders or, when present in quantities greater than therapeutic quantities, as additives to fodders in animal husbandry.

The following examples illustrate the invention.

Example 1 25 grams of N-(2-chlorethyl)-N'-[S-nitrothiazolyl- (2)]-urea in 1 liter of water are stirred and heated for 7 hours to the boil. The precipitate formed is filteredolf and recrystallized from dimethylformamide+methanol,

to yield l-[5-nitrothiazolyl-(2)1-2-oxo-tetrahydro-imidazole of the formula are evaporated, the precipitate formed is suctioned oif and thoroughly washed with warm isopropyl ether, to yield N- (Z-chlorethyl) -N- S-nitrothiazolyl) 2) -urea in 'crystals melting at 140 C. with decomposition.

Example 2 25 g. of N-(Z-chloropropyl)-N'-[5-nitrothiazolyl- (2)]-urea are boiled for 4 hours in a solution of 14 g. of sodium acetate in 200 cc. of water. The precipitate which forms is filtered off and recrystallized from dimethyl formamide-i-ethanol. There is thus obtained the 1-[5-ni trothiazolyl-(2)]-2-oxo-5-methyl-tetrahydroimidazole of the formula in the formof yellow crystals of melting point 237- 23 8" C.

The urea used as starting material can be prepared as follows: I

To a suspension of 5 g. of potassium carbonate in 50 cc. of acetone are added 14.5 g. of Z-amino-S-nitro-thiazole and 12 g. of 2-chloro-propylisocyanate. The mixture is stirred at the boiling temperature for 3 hours and the precipitate that forms is filtered off and washed with water. The filter residue is recrystallized from ethanol+water. There is obtained N-(2-chloro-propyl)-N'-[5-nitrothiazolyl-(2)]-urea in the form of crystals which melt at l70-172 C. Example 3 22 g. of N-[2-chloro-butyl-(3)]-N'-[5-nitro-thiazolyl- (2)]-urea are heated at C. for 10 minutes with 13 g. of sodium acetate in 40 cc. of dimethyl formamide. There are then added 200 cc. of water, and the precipitate which forms is filtered off. The filter residue is washed with lN-sodium hydroxide solution and, for further purification recrystallized from dimethyl formamide-l-ethanol. There is obtained the l-[S-nitrothiazolyl-(Z)]-2-oxo-4:5- dimethyl-tetrahydroi-midazole of the formula CH: CH3

in the form of yellow crystals of melting point 242- 243 C.

The urea used as starting material is prepared as follows:

14 g. of 2-amino-5-nitrothiazole are heated to 100? C. for four hours with 12 g. of 2-chloro-butyl-(3)-isocyan-ate in 100 cc. of absolute tetrahydrofuran. The solution is then evaporated to dryness under reduced pressure. The residue is recrystallized from ethanol to obtain N-{Ze chloro butyl (3)] N [5 nitro thiazolyl (2)],- urea in the form of crystals melting at C.

Example 4 15 g. of l-[4-phenyl-thiazolyl-(2)]-[2-oxo-tetrahydroimidazole are introduced into 50 cc. of concentrated sulfuric acid in such manner that the temperature does not rise above 1 0 C. After that, 7 g. of concentrated nitric acid are slowly added dropwise, and the mixture stirred at room temperature for 5 hours. The reaction mixture is poured on to ice. Aprecipitate forms which is filtered off and recrystallized from dimethyl formamide. The 1- [4 para nitrop henyl 5 nitro-thiazolyl (2)] 2 0x0 -tetrahydroimidazo le of the formula 7 is obtained in the form of yellow crystals of melting point 2-862=88 C.

The 1 [4 phenyl thiazolyl (2)] 2 oxo tetrahydroimidazole used as starting material can be prepared as follows:

1'0 g. of 2-chloro-ethyl-isocyanate are added to 10 g. of 2-amino-4-phenyl-thiazole in 50 cc. of dimethyl formamide and the mixture heated at 80 C. for 2 hours. The mixture is then cooled treated with water, and the precipitate that forms recrystallized from ethanol. There is thus obtained N-[4-phenyl-thiazolyl-(2)]-N-(2-chlorethyl)-urea of melting point 173-174 C.

10 g. of the urea are heated at 110 C. for 30 minutes with 6 g. of sodium acetate in 10 cc. of dimethyl formamide. There are then added 300 cc. of water. The precipitate which forms is recrystallized from aqueous dimethyl formamide to obtain 1-[4-phenyl-thiazolyl-(2) 2-oxo-tetrahydro-imidazole in the form of white crystals melting at 250-252" C.

Example A mixture of 16.0 g. of 2-amino-4-methyl-5nitrothiazole, 11.0 g. of fi-chlorethylisocy-an ate, 5.0 g. of potassium carbonate, and 150 cc. of acetone is stirred while being boiled for 17 hours, N-(2-ohlorethyl)-N-[4-methyl 5- nitro-thiazolyl-( 2) ]-urea being intermediately formed and partly cyclized. The batch is then cooled, treated with 200 cc. of water, and the resulting precipitate, which is a mixture of N- (2-chloroethyl) -N'-[4 methyl-5-nitro-thia zolyl- (2) ]-urea and 1- [4-methyl-S-nitro-thiazolyl-( 2) ]-2- oxo-tetra-hydro-imidazole, is filtered 01f. The residue is introduced into 50 cc. of dimethyl formamide and, after the addition of 10.0 g. of sodium acetate, heated at 100 C. for 30 minutes. Water is then added and the resulting precipitate recrystallized from dimethyl-formamide +ethanol. 1 [4 methyl 5 nitro thiazolyl (2)]- 2-oxo-tetrahydro-imidazole of the formula CHs N o|Hz(|3Hi NOz N NH is obtained in the form of yellow crystals of melting point 241-243 C.

Example 6 grams of 1-[5-nitrothiazolyl-(2)]-2-oxo-tetrahydroimidazole are dissolved in 40 cc. of dimethyl-formamide. 50 cc. of a 30% formaldehyde solution in water are then added followed by 0.5 cc. of an 80% solution of benzyltrimethyl-ammoniumhydroxide in methanol. After the reaction mixture has :been allowed to stand for 2 hours at room temperature, 1 [5 nitrothiazolyl (2)] 2 oxo- 3-hydroxymethyl-tetrahydroimidazole of the formula Example 7 is obtained in the form of crystals melting at 278 to 280 C.

Example 8 8.7 grams of 1-[4-methyl-5-nitrothiazolyl-(2)]-2-oxotetrahydroimidazole are dissolved in 30 cc. of dimethylformamide at C. 2 drops of an 80% solution of benzyltrimethylammoniumhydroxide in methanol and 50 cc. of formalin of 40% strength are then added. After one hour, 200 cc. of water are added to the solution and the precipitate is recrystallized from methanol to yield 1-[4-methyl 5 nitro thiazolyl-(2)]-2-oxo-3-hydroxymethyl-tetrahydroimidazole of the formula CHaN l [pm-pm OzN N N-OI-Ir-OH in the form of yellow crystals melting at 153-154 C.

Example 9 is obtained in the form of crystals melting at 260 C. with decomposition.

Example 10 1.2 grams of sodium hydride are added to ml. of dimethyl sulfoxide and the whole is heated for 2 hours at 70 C. with stirring. The reaction mixture is cooled to room temperature, 10 grams of 1-[5-nitrothiazolyl- (2)]-2-oxo-tetrahydroimidazole in 50 ml. of dimethyl sulfoxide are added dropwise and the batch stirred for 30 minutes. 8.0 grams of diethylaminoethyl chloride are then added dropwise. After stirring for 4 hours at 20- 25 C. excess sodium hydride is destroyed by the addition of a little ethanol. On the addition of water, a brown precipitate settles which is filtered and dissolved in 2 N acetic acid. The solution is treated with active carbon, filtered and rendered neutral by the addition of sodium carbonate. l-[5-nitrothiazolyl-(2)]-2-oxo-3-(fldiethylaminoethyl)-tetrahydroimidazole of the formula lu OzN \S/ N\ /NCI-I2-CH2-N(C2H5)2 precipitates in the form of crystals melting at -141" C.

Example 11 2 drops of an 80% Solution of benzyltrimethylammoniumhydroxide in methanol and then 30 ml. of a formaldehyde solution of 30% strength are added to a solution of 8.0 grams of 1-[5-nitrothiazolyl-(2)]-2-oxo-5- methyl-tetrahydroimidazole in 30 ml. of dimethylformamide at 80 C. The batch is cooled to room temperature and after 8 hours 200 ml. of Water are added. A precipitate of v1- -nitrothiazolyl-( 2) -2-oxo-3-hydroxymethyl-S-methyl-tetrahydroimidazole of the formula CHa settles which, after recrystallization from methanol, melts at 170-174 C.

Example 12 I 13.0 g. of N-[S-nitrothiazolyl-(Z)]-N-(3-chloropropyll-urea are added to a solution of 7.0 g. of sodium acetate in 150 cc. of water and stirred for 3 hours at 90 C. The insoluble share is filtered oil and recrystallized from dimethylformamide, to yield crystalline 1-[5- nitrothiazolyl-(Z)]-2-oxo-hexahydropyrimidine of the formula To a warm solution of 7.0 g. of 1-[5-nitro-5-thiazolyl- (2)]-2-oxo-hexahydropyrimidine in 30 ml. of dimethylform-amide are added 2 drops of a 50% eth-anolic solution of benzyltrimethylammoniumhydroxide and 50 ml. of 40% formalin. After 1 hour the mixture is treated with 200 ml. of water and recrystallized from methanol to obtain crystals of 1-[5-nitrothiazo1yl-(2)]-3-hydroxymethyl-2-oxo-hexahydpopyrimidine of the formula i CH2 N W1 1i which melt at 158 to 160 C.

Example 14 A mixture of g. of 1-[5-ni-trothiazolyl-(2)]-2-oxotetrahydroimidazole and 50 ml. of acetic anhydride is boiled for 4 hours and then allowed to cool to room temperature. The precipitate formed is filtered off and recrystallized from dimethyl-formamide+ethanol, to yield 1 [5 nitrothiazolyl-(2)]-2-oxo-3-acetyl-tetrahydroimidazole of the formula in yellow crystals melting at 163 to 166 C.

10 Example 15 The new compounds can be used in the form of pharmaceutical preparations, the daily dose being 0.1 to 10 mg. per kg. of body weight. Administration can be carried out, for example, in the form of capsules containing the desired amount of the active substances, above all 1 [S-nitrothiazolyl-(Z) -2-oxo-hexahydropyrimidine.

For use as additives to animal fodder, for example chickenfeed, the new compounds, especially 1-[5-nitrothiazolyl-(2)]-2-oxo-hexahydropyrirnidine can be mixed, for example, with cerelose (content of active compounds, for example, 0.1 to 1%, preferably 0.5%). This preliminary mix can be added to the fodder in the usual manner, advantageously so that the mixture contains about 0.01% of the pyrimidine derivative.

Example 16 Tablets containing 500 mg. of 1-[5-nitrothiazo1yl-(2)- Z-oxo-tetrahydroimidazole may be prepared with the following ingredients:

Per tablet, mg. 1- [5 -nitrothiazolyl- (2) -2-oxotetrahydroimidazole 500.0

Wheat starch 40.0 Colloidal silicic acid with hydrolysed starch 30.0 Arrowroot 30.0

Magnesium stearate 6.0 Talc 19.0

METHOD Half of the wheat starch is pasted with four times the quantity of Water on a w-aterbath. 1-[5-nitrothi'azolyl- (2)]-2-oxo-tetrahydroimidazole is homogeneously mixed with the remaining starch, then kneaded with the paste and with a sufficient quantity of water to form a plastic mass. The colloidal silicic acid with hydrolysed starch is then worked in portions.

The plastic mass is passed through a sieve having a 4-5 mm. mesh and dried at 45 C. The dried granulate is passed through a sieve of 0.8-1.4 mm. mesh and the remaining disintegrating and lubricating agents are then added. After further homogenisation tablets having a diameter of 11.5 mm. and weighing 625 mg. are compressed in the conventional manner.

In the same manner, tablets containing 1-[5-nitrothiazolyl (2)]-2-oxo-3-(hydroxymethyl)-tetrahydroimidazole can be prepared.

Example 17 v 7.8 g. of ,B-chloro-tertiary butylisocyanate in 15 ml. of acetone are added dropwise to 9.0 g. of 2-amino-5-nitrothiazole and 5.0 g. of anhydrous potassium carbonate in 60 ml. of acetone, and the mixture heated for minutes at 45 C. ml. of 2 N-hydrochloric acid are then added. The precipitate which forms is dissolved in 40 ml. of dimethyl formamide and the solution, after addition of 12.0 g. of sodium acetate, heated at 100 C. for 30 minutes. After cooling to room temperature, 100 ml. of water are added, and the resulting precipitate recrystallized from alcohol. There is obtained the 1-[5- nitro thiazolyl (2) ]-2 oxo 4,4-dimethyl-tetrahydroimidazole of the formula N CH3 1 l eat-e OzN N NH in the form of yellow crystals melting at 221-224 C. The p-chloro-tertiary butylisocyanate (boiling at 53- 56 C. under a pressure of 22 mm. Hg) used as starting material can be obtained from fi-hydroxy-tertiary butylamine by reaction with thionyl chloride to form the 8- chloro-tertiary butylamine hydrochloride, and treatment of the latter with phosgene by the method of W. Siefken, Ann. 562, 75 et seq. (1949).

Example 18 2.5 g. of 1-[5-nitro-thiazolyl-(2)]-2-oxo hexahydropyrimidine, 0.33 g. of paraformaldehyde, and 0.9 g. of dimethylamine hydrochloride in 25 cc, of dimethyl formamide are heated at 100 C. for 2 hours. The precipitate is filtered off with suction and recrystallized from 2 N-hydrochloric acid. The I-[S-nitro-thiazolyl-(Z)] 2- oxo-3(dimethylaminomethyl)-hexahydro-pyrimidine hydrochloride of the formula C OzN LS f? H2 I melts and decomposes at 258 C.

Example 19 20.0 g. of l-[S-nitro-thiazolyl-(Z)]-2-oxo tetrahydroimidazole and 800 g. of chloracetic anhydride are heated together at 120 C. for 4 hours. After cooling, the reaction mixture is treated with 200 ml. of alcohol and filtered. The filter residue is recrystallized from aqueous dimethyl formamide. The resulting crystals of 1-[5-nitro-thiazolyl- (2)]-2-oxo-3-(chloroacetyl)-tetrahydro-imidazole of the formula melt at 170173 C- Example 20 10.0 g. of 1-[5-nitro-thiazolyl-(2)]-2-oxo-tetrahydroimidazole are stirred and heated at 150 C. for 4 hours with 20.0 g. of benzoic anhydride. The reaction mixture is then recrystallized from dimethyl formamide to obtain 1-[5-nitro-thiazolyl-(2)]-2-oxo-3 benzoyl tetrahydroimidazole of the formula in the form of yellow crystals melting at 273 C.

Example 21 10.0 g. of 1-[4-methyl-5-nitrothiazolyl-(2)] 2 oxotetrahydro-imidazole are heated at the boil for 4 hours with 50 ml. of acetic anhydride. After cooling, a precipitate forms which is recrystallized from dioxane. There is obtained in this manner 1-[4-methyl-S-nitrothiazolyl- (2)]-2-oxo-3-acetyl-tetrahydro-imidazole of the formula which melts at 213-215 C.

Example 22 At C., 20 ml. of concentrated nitric acid are stirred into a solution of 5.0 g. of l-[thiazolyl-(2)]-3-acetyl-2- oxo-tetrahydro-imidazole in 50 ml. of concentrated sul- Example 23 10.0 g, of 1-[4-(para-nitrophenyl)-5-nitro thiazolyl- (2)]-2-oxo-tetrahydro-imidazole and 50 ml. of acetic anhydride are stirred while being heated at C. for 4 hours. After cooling, the precipitate that has formed is filtered off and recrystallized from aqueous dimethylformamide. There is obtained the 1-[4-(para-nitrophenyl)-5- nitro-thiazolyl-(2) ]-2-oxo-3-acetyl-tetrahydro imidazole of the formula Q OHHH.

\ lf/ Ii in the form of yellow crystals of melting point 245- 247 C.

Example 24 2.0 g. of l-[5-nitrothiazolyl-(2)1-2-oxo hexahydropyrimidine in 5 .0 ml. of dimethylformamide are heated at C. for 2 hours with 5.0 ml, of acetic anhydride. After cooling, 50 ml. of water are added, and the batch extracted with 50 ml. of methylene chloride. The methylene chloride layer is separated and evaporated under vacuum. There remains a crystalline residue of 1-[5-nitrothiazolyl- (2) 1-2-oxo-3-acetyl-hexahydropyrimidine of the formula om N l on. on. OzN N NC'OHa s II which after being recrystallized from a mixture of methylene chloride and petroleum ether melts at 220-223 C.

Example 25 10.0 g. of 1-[5-nitrothiazolyl-(2)]-oxotetrahydro-imidazole are heated at 150 C. for 4 hours with 50.0 g. of butyn'c anhydride. After cooling, ethanol is added and the batch filtered. The filtrate is evaporated, .and the residue recrystallized from aqueous ethanol. The 1-[5- nitrothiazolyl-(Z) -2-oxo-3-butyryl-tetrahydro imidazole of the formula is obtained in the form of yellow crystals melting at 143- 145 C.

Example 26 =3 m1. of concentrated nitric acid are added at room temperature to a solution of 10 g. of l-[thiazolyl-(2)]-2-oxo- 3-(fi-diethylaminoethyl)-tetrahydro-imidazole in 75 ml. of concentrated sulfuric acid. The reaction mixture is stirred for 8 hours at room temperature, then poured on to ice and carefully neutralized by the addition of ammonia. Aprecipitate settles out which is recrystallized from alcohol it melts at 142143 C.

0. 0075% of compound II as coccidiostatic ingredients:

13 from alcohol to yield 1 [5 nitro -thiazo1yl (2)] 2- oxo 3 (B diethylamino ethyl) -'tetrahydro-imidazole of the formula in the form of yellow crystals melting at 140-141 C.

The 1 [thiazolyl (2)] 2 oxo 3 (B diethylaminoethyl) tetrahydro imidazole used as starting material is prepared as follows:

17 g. of 1 [thiazolyl (2)] 2 oxo tetrahydroimidazole are added to a suspension of 2.4 g. of sodium hydride in 200 ml. of toluene, and the whole is heated for 2 hours at 90 C. The reaction mixture is cooled to 50 C., and 15 g. of [3 diethylamino ethyl chloride are added dropwise. The batch is heated for 4 hours at 90 C., 50 ml. of alcohol are then added at room temperature, the reaction mixture evaporated in vacuo, and the residue distilled in a high vacuum. 1 [Thiazolyl- 2)] 2 oxo 3 (B diethylaminoethyl) tetrahydroimidazole distills at 163-165 C. under 0.1 mm. pressure.

Example 27 The precipitatewhich forms is filtered off and washed with acetone. There is obtained in this manner 1 [5- nitrothiazolyl (2)] 3 methyl 2 oxo tetrahydroimidazole (2) of the formula which melts at 239-241" 0.

The 1 [thiazolyl (2)] 3 methyl- 2 -oxo'- tetrahydro-imidazole may be prepared as follows:

To a solution of 15.0 g. of Z-amino-thiazole in 150 m1. of boiling ether are slowly added dropwise 16.0 g.

of B chlorethylisocyanate. When the mixture is allowed to stand for a while, the N [thiazolyl (2)] N (fichlorethyl) urea crystallizes. After being recrystallized g. of the chlorethyl urea are boiled for 4 hours with 300 ml. of water. The precipitate which forms is filtered off and recrystallized from dimethylf-ormamide+methanol. There is obtainedjl [thiazolyl (2)] 2 oxo tetrahydro imid-azole in the form of white crystals of melting point 209-210 C. I

10.0 g. of 1 [thiazolyl (2)] 2 oxo tetrahydroimidazole are added to a suspension of 1.5 g. of sodium hydride in 100 ml. of toluene and the mixture stirred while being heated at 80 C. for 1 hour. There are then slowly added 8.0 g. of dimethyl sulfate, and, after 4 hours, the batch cooled to room temperature and filtered. The filtrate is evaporated under reduced pressure. The residue .is recrystallized from methanol and 1 [thiazolyl- (2)]- 3 methyl 2.- oxo tetrahydro imidazoleobtained in the form of crystals melting at 128-430 v Example 28 Chick Starter containing 0.005% of compound I and 1:1 [5 nitrothiazolyl(2)] 2 oxo tetrahydroimidazole II: 2 su-lfanilamido- 6 chloropyrazine 75.0

10 lb. of. the vitamin composition contain: 16,000,000 I.U. Vit. A, 1,000,000 LU. Vit. D 5,000 I.U. Vit. E acetate, 6 g. Vit. K 6 mg. Vit. B 3 g. riboflavin, 30 g. niacin, 5 g. calcium p-antothenate and g. ethoxyquin, made up to 10 lb. with corn meal.

The compounds I and II are first premixed with a small amount (about 2 lbs.) of the feed mixture (which is supplied as such by the manufacturer). The premix is increased to about 50 lbs. and then thoroughly mixed with the main batch in a horizontal mixer.

Example 29 A premix containing one percent of 1-[5-nitro-thiazolyl- (2) ]-2-oxo-tetrahydroimidazole is prepared as follows (for 1000 g):

Ingredients: G.

1 [5 nitr-o thiazolyl (2)] 2 oxo tetrahydroimidazole 10.00

Sugar, confectioners 100.00

Soybean feed, solvent extracted 890.00

,T he ingredients are thoroughly mixed in appropriate mixing equipment. The premix is then added to the feed formula in desired quantities.

Feed formula: G.

Corn. meal 502,000.0 Soybean meal, 44% protein 226,800.0

Alfalfa meal .18,144.0 Meat and bone meal 45,3600 'Whey, dried 9,072.0

Distillers dried solubles 22,6800 Fish meal 5 8,800.0 v Oil l Vitamin premix 2,268.0 Mineral premix 907.2 Sodium chloride 2,268.0 Menadione sodium bisulp-hite Niacin The feed formula is prepared as previously shown; the

Vitamin premix has the following ingredients Vitamin A, USP units 4,000,000 d-Pantothenic acid, g. 3,680.0 Riboflavin, g. 4.0

Vitamin B g.

Vitamin D USP units 2,000,000

Vitamin E,'I units 2,500

whereas the Mineral premix contains the following essential minerals Percent Manganese l 6.00 Iodine 0.12 Iron 2.00 Copper 0.20 Zinc 2.00 Cobalt c 0.02 Calcium 25.20

The premix is added to the above feed formula in an amount sufficient to provide concentrations of 0.5 g. and 1.0 g. of 1-[5nitro-thiazolyl-(2)]-2-oxo-tetrahydr0imidazole per 1,000 g. of feed.

What is claimed is:

1. A feedstuif composition comprising (1) a nitrothiazolyl compound of the formula in which Z represents a member selected from the group consisting of straight and branched lower alkylene separating the two nitrogen atoms by 2 to 5 carbon atoms and straight and branched lower alkylene separating the two nitrogen atoms by 2 to 5 carbon atoms and substituted by at least one member selected from the group consisting of lower alkenyl, phenyl, lower alkyl-phenyl, lower" alkoXy-phenyl, halogenphenyl, trifiuoromethyl-phenyl, nitrophenyl, phenyl-lower alkyl, lower alkyl-phenyl-lower alkyl, lower alkoxy-phenyl-lower alkyl, halogeno-phenyllower alkyl, trifluoromethyl-phenyl-lower alkyl and nitrophenyl-lower alkyl, R represents a member selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, phenyl-lower alkyl, lower alkylphenyl-lower alkyl, lower alkoxy-phenyl-lower alkyl, halogeno-phenyllower alkyl, trifluoromethyl-phenyl-lower alkyl, nitrophenyl-lower alkyl, hydroxy-lower alkyl, lower alkanoyl, halogenated lower alkanoyl, benzoyl, lower alkyl-benzoyl, lower alkoxy-benzoyl, halogeno-benzoyl, trifluoro-methylbenzoyl, aminobenzoyl, nitrobenzoyl, phenyl-lower alkanoyl, lower alkyl-phenyl-lower alkanoyl, lower alkoXyphenyl-lower alkanoyl, halogeno-phenyl-lower' alkanoyl, trifluoromethyl-phenyl-lower alkanoyl, amino-phenyllower alkanoyl, nitrophenyl-lower alkanoyl, phenyllower alkenoyl, lower alkyl-phenyl-lower alkenoyl, lower alkoxy-phenyl-lower alkenoyl, halogeno-phenyl-lower alkenoyl, trifiuoromethylphenyl-lower alkenoyl, aminophenyl-lower alkenoyl, nitro-phenyl-lower alkenoyl, pyridoyl, lower alkyl-pyridoyl, lower alkoXy-pyridoyl, halogenopyridoyl, trifluoromethyl-pyridoyl, aminopyridoyl, nitropyridoyl, furoyl, lower alkylfuroyl, lower alkoxy-furoyl, halogenofuroyl, trifluoromethylfuroyl, 'aminofuroyl, nitrofuroyl, thiophenecarbonyl, lower alkyl-thiophenecarbonyl, lower alkoXy-thiophenecarbonyl, halogeno-thiophenecarbonyl, trifluoromethyl-thiophenecarbonyl, amino-thiophene-carbonyl and nitrothiophenecarbonyl and a radical of the formula N l I OaN N NR- H o in which a'lk stands *for a member selected from the group consisting of straight and branched lower alkylene separating the two nitrogen atoms by 2 to 5 carbon atoms and R stands for a member selected from the group consisting of hydrogen, lower alkyl, hydnoxy-lower alkyl, dilower alkyl amino-lower alkyl, lower alkanoyl, benzoyl, lower alkyl-benzoyl, halogeno-benzoyl, lower alkoxybenzoyl, trifluorome'thyl-benzoyl and nitrobenzoyl.

3. A feedstuff composition as claimed in claim 1, in which the nitrothiazolyl compound is I-[S-nitro-thiazolyl- (2) -2-oxo-tetrahydroimidazole.

4. An animal feedstuif additive composition comprising (1) a compound of the formula in which Z represents a member selected from the group consisting of straight and branched lower alkylene separating the two nitrogen atoms by 2 to 5 carbon atoms and straight and branched lower alkylene separating the two nitrogen atoms by 2 to 5 carbon atoms and substituted by at least one member selected from the group consisting of lower alkenyl, phenyl, lower alkyl-phenyl, lower alkoxy-phenyl, halogen-phenyl, trifluoromethy-phenyl, nitrophenyl, phenyl-lower alkyl, loweralkyl-phenyl-lower alkyl, lower alkoxy-phenyl-lower alkyl, halogeno-phenyllower alkyl, trifluoromethyl-phenyl-lower alkyl and nitrophenyl-lower alkyl, R represents a member selected from the group consisting of hydrogen, lower alkyl, lower :alkenyl, phenyl-lower alkyl, lower alkyl-phenyl-lower alkyl, lower alkoxy-phenyl-lower alkyl, halogeno-phenyllower alkyl, trifluoromethyl-phenyl-lower alkyl, nitrophenyl-lower alkyl, hydroxy lower alkyl, lower alkanoyl, halogenated lower alkanoyl, benzoyl, lower alkyl-benzoyl, lower alkoxy-benzoyl, halogeno-benzoyl, trifl-uoro-methylbenzoyl, amino benzoyl, nitrobenzoyl, phenyl-lower alkanoyl, lower alkyl-phenyl-lower alkanoyl, lower alkoxyphenyl-lower alkanoyl, halogeno-phenyl-lower alkanoyl, trifluoromethyl-phenyl-lower alkanoyl, aminophenyl-lower alkanoyl, ni-tro-phenyl-lower alkanoyl, phenyl-lower alkenoyl, lower alkyl-phenyl-lower alkenoyl, lower alkoxyphenyl-lower alkenoyl, halo geno-phenyl-lower alkenoyl, trifluoromethyl-phenyl lower alkenoyl, aminophenyl-lower alkenoyl, nitro-phenyl-lower alkenoyl, pyridoyl, lower alkyl-pyridoyl, lower alkoXy-pyridoyl, halogenopyzri'doyl, triflu-oromethyl-pyridoyl, amino-pyridoyl, nitropyridoyl, furoyl, lower alkylfuroyl, lower alk-oxy-furoyl, halogenofuroyl, trifluoro-methylfuroyl, amino-fiuroyl, nit-nofuroyl, thiophenecarbonyl, lower alkyl-thiophene-carbonyl, lower alkoxy-thiophenecarbonyl, halogeno-thiophene-canbonyl, trifl-uoromethyl-thiophenecarbonyl, amino-thiophenecarbonyl and nitrothiophenecarbonyl and a radical of the formula in which R and R each stands for a member selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower cycloalkyl and, when taken together, alkylene, mono-oXa-alkylene and mono-aza-al kylene having from 4 to 8 carbon atoms, alk for lower alkylene and R stands 'for a member selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, phenyl, lower a-lkylphenyl, lower alkoxyphenyl, halo'genophenyl, trifiuoromethyl-phenyl and nitrophenyl and (2) a feedstuif, said nitrothiazo'lyl compound being present in a quantity greater than the therapeutic quantity.

5. An animal feedstufi additive composition as claimed 1 7 in claim 4, in which the nitrothiazolyl compound is one of the formula in which alk stands for a member selected from the group consisting pfstr-aight and branched lower alkylene separating theztwo nitrogen atoms by 2 to 5 carbon. atoms and R stands for a member selected from the group consisting of hydrogen, lower alkyl, hydroxy-l'ower alkyl, di-

lower, a1kyl=amino-lower alkyl, lower :alkanoyl, benzoyl, lower alkyl-beiizoyl, halogeno benzoyl, lower alkoxy b enzoyl, trifluoromethyl benzoyl and nitrobenzoyl.

6. An animal feedstulf additive composition as claimed in claim 4, 'which the nitrothiazolyl compound is l-[5 nitro-thiazolyl- 2) ]-2-oxo-tetrahydroimidazole.

7. A feedstulf composition comprising (1) an acid addition salt of a compound of the formula in which Z represents a member selected from the group consisting of straight and branched lower alkylene separating the two nitrogen atoms by 2 to 5 carbon atoms and straight and branched lower alkylene separating the two nitrogen atoms by 2 t carbon atoms and substituted by at least one member selected from the group consisting of lower alkenyl, phenyl, lower alkyl-phenyl, lower :alkoXy-plenyl, halogenphenyl, trifluoromethyl-phenyl, nitrophenyl, phenyl-l-ower alkyl, lower alkyl-phenyl-lower alkyl, lower alkoxy-phenyl-lower alkyl, ha-logeno-phenyllower alkyl, trifi uoromethyl-phenyl-lower alkyl and nitro phenyl-lower alkyl, R and R each stands for a membel selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower cycloalkyl and, when taken together, alkylene, mono-oxa-alkylene and mono-aZa-alkylene having from 4 to 8 carbon atoms, alk bor lower alkylene and R stands for a member selected from the group consisting of hydrogen, lower alkyl, lower alken-yl, phenyl, lower alkylpenyl, lower alkoxy-phenyl, halogenophenyl, trifiuoromethyl-phenyl-and nitrophenyl and (2) an animal feedstuff.

8. An animal feedstufi additive composition comprising (1) an acid addition salt of a compound of the formula in which Z represents -a member selected from the group consisting of straight and branched lower alkylene separating the two nitrogen atoms by 2 to 5 carbon atoms and straight and branched lower alkylene separating the two nitrogen atoms by 2 to 5 carbon atoms and substituted by at least one member selected from the group consisting of lower alkenyl, phenyl, lower alkyl-phenyl, lower alkoxy-phenyl, halogenphenyl, trifluoromethyl-phenyl, nitrophenyl, phenyl-lower alkyl, lower alkyl-phenyllower alkyl, lower alkoxy-phenyl-lower alkyl, halogenopheny-lower alkyl, trifluoromethyl-phenyl-lower alkyl and nitrophenyl-lower alkyl, R and R each stands for a member selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower cycloalkyl and, when taken together, alkylene, mono-oxa-alkylene and monoaza-alkylene having from 4 to 8 carbon atoms, alk for lower 'alkylene and R stands for a member selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, phenyl, lower alkylphenyl, lower alkoxyphenyl, halogenophenyl, trifluoromethyl-phenyl and nitrophenyl and (2) a feedstuff, said nitrothiazolyl compound being present in a quantity greater than the therapeutic quantity.

References Cited by the Examiner UNITED STATES PATENTS SAM ROSEN, Primary Examiner.

R. BARRESE, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No a 3, 298, 914 January 17, 1967 Paul Schmidt et ale It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

I Column 1, lines 20 and 21, for "diazoeach occurrence, read diazacolumn 3, line 26, for "2oxohexa-" read 2-oxohexacolumn 10, line 6, for "substances read substance line 18, for "2)-" read 2)] column 12, line 51, for "oxotetrahydro" read oxo-tetrahydro column 16, line 9, for (2) read (2)] n Signed and sealed this 28th day of November 1967.

(SEAL) Attest:

EDWARD J. BRENNER Edward M. Fletcher, Jr.

Commissioner of Patents Attesting Officer 

1. A FEEDSTUFF COMPOSITION COMPRISING (1) A NITROTHIAZOLYL COMPOUND OF THE FORMULA 